Asthma is a major cause of morbidity and mortality in the world and is estimated to affect around 300 million people worldwide. It is estimated that an additional 100 million people will suffer from asthma in 2025. The increasing prevalence especially affects children. Currently, asthma is the death cause for 1 out of 250 deaths, which in many cases is due to insufficient treatment (www.ginasthma.com).
Although the exact cause of asthma is not fully understood, it is known to be characterised by inflammation of the airways and a decline in respiratory function. In asthma, a number of inflammatory cells, including eosinophiles and CD4+ T-lymphocytes are thought to contribute to the pathogenesis of the disease. Further important features are the presence of airway wall remodelling, hyperplasia/hypertrophy of airway smooth muscle, increased collagen deposition beneath the basement membrane, increased mucus production, angiogenesis and alterations in extracellular matrix (Bousquet et al. Asthma—from bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000; 161(5):1720-1745). Furthermore, there are reports suggesting that severe viral infections in infants are a risk factor for airway hyperresponsiveness and bronchial asthma in later life (Hashimoto et al. DSCG Reduces RSV-Induced Illness in RSV-Infected Mice. J Med Virol 2009; 81:354-361).
Disodium cromoglycate (DSCG) is a safe and widely used drug for the prevention of bronchial asthma, allergic rhinitis and conjunctivitis attacks. It is recommended in current guidelines for treatment of asthma, such as the guidelines published by the Global Initiative for Asthma (GINA), as an alternative therapy for the standard recommended glucocorticosteroids, long-acting β2-agonists, theophylline and leukotriene modifiers.
The first choice therapy recommended for long-term management of asthma in European, US and Japanese guidelines is inhalation of corticosteroids. Although these guidelines note that currently available inhaled corticosteroids are safer, they also warn that chronic use of inhaled corticosteroids initiated in childhood and continued through adulthood might have cumulative effects that increase the relative risk of certain conditions such as osteoporosis, cataract or glaucoma in later life. Due to these and other side effects, it is not always justifiable to use inhaled corticosteroids for treatment of mild asthma, especially in young children. In contrast, DSCG has a safety profile encompassing more than 35 years of clinical use. The majority of controlled, direct comparisons of DSCG and inhaled corticosteroids in children with mild-to-moderate asthma showed comparable efficacy. Some of these studies have also shown a reduction of the needed inhaled corticosteroid dose for some patients when DSCG was added to their treatment regimen (e.g. Petersen et al. Sodium cromoglycate as a replacement for inhaled corticosteroids in mild-to-moderate childhood asthma. Allergy 1996; 51: 870-875). For patients with more severe disease, whose asthma is not optimally controlled despite maximal doses of inhaled corticosteroids, DSCG provides a safe and flexible option for added symptom relief with the promise of lowering the dose of corticosteroids.
Summarised from several studies, it can be stated that the anti-asthmatic effects of DSCG are related to stabilization of the mast cell membrane, suppression of eosinophil activation, suppression of accumulation of T-lymphocytes and eosinophils, suppression of the formation of IL-5 by peripheral mononuclear cells, suppression of excitation of the sensory nerve C-fibre, suppression of the expression of adhesion molecules, and suppression of IgE formation. These findings are based on both in vitro and in vivo evaluations. In the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (COPD), it is thought to be critical to reduce the inflammatory response in the airways in order to reverse many of the changes seen in these diseases.
Another field where DSCG is often used is the treatment of diseases of the eye. The compound has been shown to have a positive effect when utilized in allergic eye conditions, vernal conjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis. Again, the mechanism of action is based on the stabilization of mast cells.
Furthermore, some antiviral effects are attributed to DSCG. For example, Kazuya et al. (In vitro and in vivo inhibitory effects of disodium cromoglycate on influenza virus infection. Biol Pharm Bull 2004; 27: 825-830) showed in a murine model of respiratory tract infection that DSCG protected mice from death induced by infection with an influenza virus. The effective dose was similar to the dose used in the treatment of asthma. Furthermore, Hashimoto et al. (DSCG reduces RSV-induced illness in RSV infected mice. J Med Virol 2009; 81:354-361) recently showed that mice treated with DSCG are protected against respiratory syncytial virus induced illness and have decreased viral inflammation. However, the mechanism of antiviral action is still being discussed and also the antiviral effect itself remains controversial.
The fact that DSCG is only recommended as an alternative treatment in asthma, is mainly based on the results of two meta-analyses (Tasche at al. Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review. Thorax 2000; 55:913-920, and van der Wouden at al. Inhaled cromoglycate for asthma in children. The Cochrane Database of Systematic Reviews 2003; 3: CD002173, 1-48). The meta-analyses were performed to overcome the generally small sample size of the available clinical trials with DSCG for the treatment of childhood asthma. Both studies concluded that there is insufficient evidence that DSCG has a beneficial effect as maintenance treatment in children with asthma in comparison with placebo. However, several concerns were raised about the interpretation of the results in these analyses (e.g. Stevens et al. Sodium cromoglicate: an ineffective drug or meta-analysis misused? Pharm Stat. 2007; 6: 123-137). It can be concluded that the clinical efficacy assessment in some of the therapeutic guidelines in childhood asthma is hampered by a major contribution of early clinical trial conduction with limited sample size and suboptimal design, unknown inhaler device performance and discussable conclusions from the two DSCG meta-analyses used as a basis for the guidelines.
Furthermore, the meta-analysis did not consider the possible influence of used delivery systems (metered dose inhalers, dry powder inhalers, and various nebulizer systems). However, it is known that, due to the larger surface area, more severe inflammatory and structural changes occur in the distal lung and lung parenchyma of asthmatic patients (Tulic and Hamid. Contribution of the distal lung to the pathologic and physiologic changes in asthma. Chest 2003; 123: 348S-355S) and that a similar but more severe inflammation process is present in the peripheral airways compared with the central airways in asthma patients (Hamid et al. Inflammation of small airways in asthma. J Allergy Clin Immunol 1998; 101:386-390). To reach these inflammation sites in the lung, particularly in children, a high percentage of the drug particles should be smaller than 3.3 μm (Keller at al. Using infant deposition models to improve inhaler system design. Proceedings Respiratory Drug Delivery IX, 2004, p. 221-231). The percentage of small particles, and thus the lung deposition, is known to be negatively affected by hygroscopic growth of particles in the humid environment of the respiratory tract (up to 99% relative humidity) (Ferron at al. Estimation of the deposition of aerosolized drugs in the human respiratory tract due to hygroscopic growth. J Aerosol Med 1989; 2: 271-284). DSCG is a very hygroscopic substance and it has been shown in a Next Generation Impactor (NGI), operated at 50 and 95% relative humidity, that the DSCG fine particle fraction declines with increasing humidity and DSCG dose and that this decline is much larger for metered dose inhalers (MDIs) and dry powder inhalers (DPIs) compared to fine mist nebulizers (Keller et al. Importance of the inhaler system and relative humidity on the fine particle dose of disodium cromoglycate. Proceedings Respiratory Drug Delivery Europe 2007, p. 307-310). A solution for this problem is presented in US 2007/0193577, where DSCG is nebulized with high efficiency nebulizers such as vibrating membrane nebulizers (e.g. eFlow nebulizer of PARI Pharma GmbH). The nebulization with such nebulizers results in an unexpectedly high amount of drug deposited in the lungs.
A clinical study (Moeller et al. European Respiratory Society Conference 2008, Poster No. 3958) showed that nebulized DSCG was therapeutically as effective as inhaled steroids. The study lasted for 6 months and compared two children cohorts suffering from atopic allergic asthma. One cohort inhaled 3 times daily IsoCrom (20 mg/2 ml) via a customized small droplet eFlow electronic nebulizer and the other cohort inhaled twice daily steroids via a metered dose inhaler with an AeroChamber. However, nebulization of 3 times 2 ml IsoCrom was rated burdensome, since some children had to inhale 3 times daily up to 10 minutes which compromised drug adherence. Thus, the development of a higher concentrated DSCG solution with the same good tolerability as IsoCrom offering shorter nebulization times and less frequent administration was most desirable.
Currently, DSCG for inhalation often needs to be used four times a day, due to the short half-life of the drug. This multiple dosing generally leads to poor compliance and diminished effectiveness of the treatment. The administered dose of DSCG largely depends on the type of formulation. With MDIs, 2 mg doses have been used, whereas with a DPI or nebulizer, the dose can be increased to 40 mg. It should also be noted that DSCG is rapidly cleared from the lungs, with 75% of the inhaled dose removed after 2 hours and more than 98% within 24 hours (Norris and Holgate, Cromolyn sodium and nedocromil sodium. In: Middleton et al. (eds) Allergy: principle and practice, 1998; St. Louis: Mosby p. 661-667).
In general, it would be an advantage to reduce the number of treatments per day, thereby increasing the compliance and the effectiveness of DSCG. Furthermore, as described above, nebulized DSCG solutions show better results regarding targeting the lower regions of the lungs. Although nebulizers are easier to use for children as MDIs or DPIs, they have the disadvantage of a longer nebulization time. In this respect, it is important for patient compliance that the nebulization time remains as short as possible.
One important issue found for DSCG solutions is the sensitivity to precipitation. EP 0 212 927 describes combined solutions of DSCG and mucolytic agents such as N-acetyl-l-cysteine, where the sensitivity of DSCG to precipitation was related to the relatively high pH (7-9) and the presence of other solutes. Stable solutions were prepared by minimizing the amount of di- and multivalent metal ions and by adding a chelating agent. The latter should ensure that no precipitation of metal salts of the cromoglycate anion occurs. The concentration of the chelating agent depended on the present concentration of metal ions: in case the latter concentration is lower than 0.40 ppm, the chelating agent can be omitted. Even when the chelating agent is incorporated, the concentration of metal ions should be less than 10 ppm. The solution may further contain conventional excipients such as sodium chloride, dextrose or mannitol, and buffers.
EP 0 413 583 describes solutions with from about 0.8 to 5% of cromolyn, where the metal ion concentration can be larger than 20 ppm. Precipitation of cromolyn is in this case prevented on the condition that there is up to about 5% (w/v) of a pharmaceutically acceptable chelating or sequestering agent, preferably sodium citrate dihydrate, added to the solution. The preferred solutions further comprise sodium chloride, potassium chloride, calcium chloride dihydrate, and sodium acetate trihydrate. The salts are used as isotonising agents. Alternatively, the document teaches the use of glycerine, mannitol, or sorbitol as isotonising agents.
EP 0 274 590 mentions that DSCG precipitation in eye drops, caused by metal ions originating from pharmaceutical glass or the rubber or plastic stoppers of vials, or by the presence of preservatives such as benzalkoniumchloride, is generally prevented by the addition of EDTA. However, as allergies to EDTA are often existing, the document presents an alternative solution, being the formulation of DSCG with sorbitol (as isotonising agent) and chlorbutanol (as preservative).
In EP 0 587 264, it is described that DSCG precipitates from highly concentrated solutions (more than 2% DSCG) when sodium chloride is used as isotonising agent. It is suggested to use non-ionic isotonising agents, but the use of usual non-ionic isotonising agents such as sugars and polyols is not preferred as they are considered as growth media for micro-organisms. Therefore, the claimed solutions are isotonised with glycerol. The DSCG concentration ranges between 3.5 to 5% (w/v).
In EP 0 933 084, the precipitation of DSCG is related to the presence of benzalkonium chloride and metal ions. The known methods of preventing this are, according to the inventors, the use of chelating agents, sorbitan, castor oil and non-ionic surfactants. The invention described here, is based on the use of 2-amino-ethanol or tocopherol for the prevention of the precipitation. The concentration of the active agent may generally be about 1.5 to 4% by weight. Sodium chloride and glycerine are described as isotonising agents.
US 2007/0193577 describes DSCG solutions for inhalation, including formulations comprising sodium chloride along with relatively small amounts of xylitol or trehalose. The document is silent about the rationale or the effects of such combination of excipients.
In summary, the prior art describing DSCG solutions suggests to avoid precipitation by reducing or avoiding the presence of metal ions, by adding chelating agents, and, when no chelating agents are used, by replacing sodium chloride by non-ionic isotonising agents.
A further important requirement for DSCG solutions for inhalation is that they are well-tolerable and non-irritating in the respiratory tract. Application WO 97/15284 describes that DSCG causes eye irritation, manifested by a strong burning sensation in the eye. This suggests that also irritation on the mucosal surfaces of the respiratory tract might occur. Therefore, attention should be given to possible irritation effects during the development of novel DSCG solutions.
The inventors found that the solutions presented in prior art do not fully solve the problems related to the formulation of highly concentrated DSCG solutions. Firstly, it was found that solutions only containing non-ionic isotonising agents are more irritating in the respiratory tract as solutions where sodium chloride is used. On the other hand, it was found that not only di- and multivalent metal ions seem to have a negative effect in DSCG solutions, but that solutions isotonised with alkali metal salts such as sodium chloride can be difficult to aerosolise. The addition of chelating agents only brings a limited solution to the problem. Therefore, it is an aim of the invention to provide improved DSCG solutions with favourable aerosolisation properties. Further aims will become apparent on the basis of the description and the patent claims.